Minerva Biotecnologica 2007 December;19(4):151-8

Protein kinases: multifaceted therapeutic targets

Protein kinases promote protein phosphorylation leading to signal transduction or enzyme regulation and represent a broad range of proteins which play important roles in regulating most cellular functions. Not surprisingly, therefore, they themselves are often oncogenes. In the early years of this century, the growing interest in developing orally active protein kinase inhibitors has culminated in the approval of the first drugs of this new pharmacological class. The first in absolute to be granted Food and Drug Administration approval was Gleevec, in May 2001. To date, about a dozen protein kinase inhibitors have reached or are about to reach the market, and are reviewed here. They are small synthetic molecules developed and approved for cancer therapy; they are not selective, but multi-target kinase inhibitors, targeting up to about 20 kinases, only four of which actually being considered to bring about therapeutic effects. Inflammatory and cardiovascular diseases and diabetes, also possible targets of protein kinases, are not covered in this paper. How selective does the activity profile of a protein kinase inhibitor have to be for it to become a drug? Does multitargeting pose a real risk of side/toxic effects or is it a winning pharmacological profile? Unlike cytotoxic drugs, many kinase inhibitors have shown low toxicity in preclinical and clinical studies, except for Gefitinib, which can cause interstitial lung disease. The pragmatic strategy followed so far, not to take too much notice of possible side-effects apart from those concerning safety pharmacology, has been successful. Indeed, the fact of being multitargeting has allowed the indications of Gleevec® and Sprycel® to be extended, since as well as inhibiting BCR/ABL, they also inhibit c-Kit. The same has happened with Sutent®. Tumoral pathology involves a network of oncological protein kinases and it is not surprising that the lack of selectivity of known inhibitors is a winning feature. Furthermore, it must be acknowledged that the toxicity and side effects observed with kinase inhibitors are negligible compared to those induced by chemotherapeutics. When protein kinase inhibitors are used for the treatment of inflammatory pathologies, however, the situation is different because a more stringent toxicology profile is desirable. Novel, ever more advanced technologies, are being developed and validated to assess the in vitro selectivity and cross-reactivity of kinase inhibitors